- In this study, a multi-omics approach was used to compare 70 individuals from rural areas of Tanzania and 253 individuals from urban areas who represented a range of lifestyles, diet and microbial exposures
- Results of stool metagenomic sequencing revealed an "urbanization gradient" of microbial composition, especially when the Tanzanians were compared with 471 historical Dutch controls
- Variation in cytokine responses, most notably tumor necrosis factor-α and interferon-gamma, was linked to 34 immunomodulatory microbes that had increased effects on independently measured circulating metabolites
- Multiple lines of evidence supported histidine and arginine metabolism as microbially-mediated immunomodulatory pathways
- Improved understanding of how microbial metabolism influences the immune system is expected to enable new individualized or population-specific therapeutic interventions
The human gut microbiome is now understood to modulate innate and adaptive immunity, but how microbial species affect cytokines is unclear.
Researchers at Massachusetts General Hospital recently studied a Tanzanian cohort representing a range of environments, lifestyles and diets, and identified 34 microbes that modulate circulating cytokines. Ramnik J. Xavier, MD, PhD, director of the Center for the Study of IBD at Mass General, Martin Stražar, of the Broad Institute, Mihai G. Netea, MD, PhD, of Radboud University Medical Center, and colleagues present this and other findings on gut microbiome-mediated metabolism effects on immunity in Nature Communications.
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The researchers compared three cohorts that were well balanced for gender:
- 70 individuals from rural areas of Tanzania
- 253 individuals from urban areas of Tanzania
- 471 individuals from the Netherlands, previously reported in Cell
All cohorts provided samples for stool metagenomic sequencing, plasma metabolomic profiling and ex vivo stimulation of whole blood with a panel of well-studied microbes.
Distinct differences in intestinal microbial composition were observed in an "urbanization gradient" from rural through urban Tanzania and the Netherlands. For example:
- Rural samples were high in Bacteroidetes, led by Prevotella copri, which is abundant in Crohn's disease, and they harbored a notable proportion of fungi
- Urban Tanzanians exhibited significantly more Actinobacteria and Verrucomicrobia than rural Tanzanians and significantly less fungi
- Urban Tanzanian samples were more similar to Dutch samples, but six species were more abundant in the Dutch, including Bifidobacterium longum and Akkermansia muciniphila; the latter has been linked to increased pro-inflammatory cytokine expression
When the immunological profiles of the Tanzanians were assessed:
- The rural population showed lower cytokine responses overall, particularly after stimulation of tumor necrosis factor-α with bacterial lipopolysaccharides, Staphylococcus aureus or Candida albicans
- Another notable cytokine was interferon-gamma, which elicited stronger responses to intracellular than extracellular stimuli, consistent with its role in lymphocyte-induced macrophage activation
- TNF-α, interleukin-6, IL-1β and IL-10 were positively correlated with monocytes, while IFN-γ was more strongly associated with lymphocytes
The rural and urban populations did not represent distinct genetic clusters, so this variation in cytokine production suggests environmental factors affected the immune responses. Concordant results were obtained in the Dutch cohort.
The variation in cytokine responses, especially TNF-α and IFN-γ, was significantly associated with 34 immunomodulatory microbes, which had a larger impact on circulating metabolites than non-significant microbes.
Urbanization-driven differences in immune responses and the impact of immunomodulatory species were further investigated by analyzing circulating metabolites:
- 1,234 metabolites were associated with cytokine expression
- TNF-α stimulated by C. albicans was associated with the most metabolites (n=685), in agreement with the microbiome analysis
- Positive immunomodulatory effects were mediated by glycerophospholipids, sphingolipids and microbially modified metabolites including histidine
- Negative effects predominantly manifested through products of tyrosine, alanine, phenylalanine and cysteine metabolism
Integrative Analysis of Metabolism Pathways
Both histamine and histidine had positive associations with cytokine expression and were encoded by positive immunomodulatory species, whereas arginine biosynthesis downregulated cytokine production. B. longum had an active role in both histidine and arginine metabolism, and A. muciniphila contributed arg genes in 33% to 36% of samples.
Mechanistic understanding of microbial metabolism and its effects on the immune system are expected to enable new individualized or population-specific therapeutic strategies or dietary interventions.
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